DESCRIPTION: Currently available antiretroviral (ARV) formulations necessitate lifelong, daily dosing, and after prolonged periods of time, patients can encounter pill fatigue and frequently miss doses of their medication. This can have detrimental consequences for the success of therapy, increasing likelihood of the virus developing resistance to the drugs used. Two pharmaceutical companies have developed sustained-release formulations, rilpivirine LA and S/GSK744, that can be administered once a month or even less frequently. However, a major limitation for these two formulations is that they are not optimally designed to be combined with each other. Additionally, the current standard of care is to administer three ARVs simultaneously. Most current ARV regimens include a class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs). A major obstacle to developing long-acting injectable combination ARVs is that NRTIs are not compatible with the technologies being utilized to produce these formulations. Using our recent developments in solid drug nanoparticle (SDN) technology, we propose to optimize a sustained-release backbone regimen consisting of NRTIs to match current standard of care and compliment sustained-release formulations in late stage development. Since NRTIs are inherently water soluble, they are not compatible with the nanomilling approaches used to create rilpivirine LA and S/GSK744. Using our new and proprietary technology we will assess two strategies for sustained-release NRTI-formulations and establish the utility for NRTI sustained- release over an extended period of time, defining a new platform technology for water soluble drugs. Iteration between pharmacology and chemistry will ensure stable nanoparticles with sufficiently high drug-loading to make viable dosage sizes with scalable and reproducible synthesis validated for sterility, stability and cost effectiveness. Nanoparticles will undergo a sequential and detailed preclinical evaluation of their pharmacology and safety, to enable optimization of favorable properties. Lead candidates will be selected for analysis in humanized mice by integrating laboratory data through mathematical modeling. We will assess candidate formulations for stability in biological fluids, release kinetic, delivery to cells and antiviral activity. This new platform for sustained-release NRTIs will benefi patients by increasing options for long-acting ARV's, thus simplifying therapy. Our collaboration combines the unique expertise of one of the world's leading centers for nanoformulation research, protected by 25 patent families, with one of the world's leading centers for ARV pharmacology research.